KR20030021630A - Process for preparing sodium thiofuroate - Google Patents

Abstract

PURPOSE: A process for preparing sodium thiofuroate is provided, thereby high quality sodium thiofuroate can be effectively prepared, and bad smell and side-products produced from a reaction process can be inhibited. CONSTITUTION: The process for preparing sodium thiofuroate represented by formula(1) comprises reacting 2-furoyl chloride represented by formula(2) with sodium sulfide in an organic solvent, wherein the organic solvent is at least one solvent selected from acetonitrile, acetone, dimethylsulfoxide, dimethylformamide, methylene chloride, 1,2-dichloroethane, methanol, ethanol, propanol, butanol, diethylether and diisopropylether; the amount of sodium sulfide reacted is 1.0 to 1.6 equivalent based on the amount of 2-furoyl chloride.

Description

Process for preparing sodium thiofuroate {Process for preparing sodium thiofuroate}

The present invention relates to a method for the efficient preparation of sodium thiofuroate in solid phase which is an important intermediate for the synthesis of ceftiofer, an animal antibiotic, and useful as a substitute for liquid thiofuroic acid.

U.S. Patent 4,464,367 discloses 7- [2- (amino-1, 3-thiazol-4-yl) -2- (methoxyimino) acetamido] -3-[(fur-2-ylcarbonyl) A cethiothio, an alkali salt, an alkaline earth metal salt, and an amine salt thereof, named -thiomethyl] -3-cefe-4-carboxylic acid, is disclosed, and 3-furoyl of the following general formula (3) is a key intermediate. The contents of thiopuroic acid and sodium thiopuroate for the preparation of thiomethyl-7-amino-3-cepem-4-carboxylic acid are known from US Pat. No. 4,937,330.

However, in the conventional manufacturing method, the reaction proceeds by adjusting pH by using water as a solvent and Na ₂ S as a reactant in preparing thiofuroic acid and sodium thiopuroate, which are intermediates of ceftiofer. Therefore, generation of H ₂ S gas was inevitable. Therefore, several extractions had to be involved to degas the H ₂ S gas in the solvent or to obtain pure thiofuroic acid. In addition, in the conventional method, it is very important to adjust the pH to a certain range, so there is inconvenience in that the pH must be checked at any time during the reaction and continuously adjusted using an acid or a base. In addition, the prepared thiopuronic acid is a liquid compound with a toxic odor, and is easy to deteriorate at room temperature, and is difficult to store and transport as products by reacting with oxygen or moisture in the air to make by-products.

Therefore, the present inventors conducted intensive studies to develop a method for efficiently preparing solid sodium thiopuroate, which can be used chemically equivalent to liquid thiopuroic acid as an intermediate of ceftiofer, and as a result, an organic solvent. The present invention has been accomplished by finding that it is possible to prepare sodium thiopuroate in a simple manner without the need for pH adjustment.

The present invention relates to a method for preparing sodium thiopuroate of the formula (1), characterized by reacting 2-furoyl chloride of the formula (2) with sodium sulfide in an organic solvent:

[Formula 2]

[Formula 1]

The method according to the present invention proceeds by first adding a certain amount of sodium sulfide (Na ₂ S) to an organic solvent and then adding a compound of formula (2) while stirring. After the addition, the color is changed to yellow and the desired sodium thiopuroate is produced. After stirring for 30 minutes, the reaction is completed after confirming that the starting material 2-furoyl chloride is completely disappeared. .

In the process according to the invention, sodium anhydride can be used both as anhydride, pentahydrate or dihydrate, but most preferably double anhydride is used. When dihydrate or pentahydrate is used, sodium thiofuroate of a quality comparable to anhydride can be produced by increasing the amount of solvent used and reacting. Sodium sulfide should be used in an amount of 1.0 equivalent or more based on 2-furoyl chloride of Formula 2 to complete the reaction. The higher the amount of sodium sulfide used, the higher the purity of the target compound can be obtained. However, from an economical point of view, such as production cost, an appropriate amount of use may refer to 1.0 to 1.6 equivalents based on the compound of Formula 2, and preferably 1.0 to 1.3 equivalents.

Organic solvents that can be used to achieve the object according to the present invention include acetonitrile, acetone, dimethyl sulfoxide, dimethylformamide, methylene chloride, 1,2-dichloroethane, methanol, ethanol, propanol, butanol, diethyl ether And at least one selected from diisopropyl ether.

The reaction temperature may be any room temperature, but is slightly exothermic during the reaction, so that the temperature does not rise, and preferably 5 to 15 ° C. In general, the reaction is terminated within 30 minutes, but it can be confirmed that the starting material 2-furoyl chloride is completely consumed after stirring for at least 4 hours depending on the solvent used. The progress of the reaction was confirmed using HPLC.

After confirming that the reaction was completed, the reaction solution was filtered to remove the produced sodium chloride and excess sodium sulfide. The filtrate containing the desired product is used directly with the solvent in the next reaction to prepare 7-ACF, or the solvent is distilled off to obtain solid sodium thiopuroate of the formula (1).

When the sodium thiofuroate of Chemical Formula 1 is prepared using the above-described method, unlike the conventional method, the operation process for adjusting pH may be omitted, and there is no generation of toxic gas during the reaction, It can be shortened to achieve safety and cost savings in the manufacturing process.

Sodium thiopuroate prepared according to the present invention may be used in the synthesis of 7-ACF, which is dissolved in the reaction solvent after filtration or immediately after the solidification process.

The synthesis process of 7-ACF proceeds as follows. Water was added to the mixed solution of the solvent and sodium thiopuroate, the pH was adjusted to 4, and then 7-aminocephalosporinic acid (7-ACA) and a base were added to increase the temperature at a pH of 5-7. The amount of water, which is a solvent, is appropriate if the amount of 7-ACA is dissolved when heated, but the more solvent, the faster the reaction progresses and the color and quality of the target compound 7-ACF are good. However, productivity is considered to determine the appropriate amount of solvent. At this time, the reaction temperature is suitable 40 to 70 ℃, was the best when the reaction proceeded at 50 to 60 ℃. As the reaction base, pH was adjusted using sodium hydroxide, sodium carbonate, sodium bicarbonate, and the like. The pH of the reaction solution is preferably 5-7. After analyzing the reaction solution by HPLC to confirm that the starting material 7-ACA is completely disappeared, the reaction is terminated, and crystals are precipitated by slowly dropping the pH to 2 to 3 using phosphoric acid or hydrochloric acid at the same temperature. After the crystals are sufficiently precipitated, the mixture is filtered at the same temperature as the reaction temperature, the solid is washed with hot water and dried.

Hereinafter, the present invention will be described in more detail based on the following examples. However, these examples are only for the understanding of the present invention, and the scope of the present invention in any sense is not limited thereto.

Example 1

Sodium sulfide (Na ₂ S) pentahydrate (1.2 mol, 201.65 g) was added to acetone (1 L), followed by rapid stirring. 2-furoyl chloride (1.0mol, 130.53g) was added over 30 minutes while maintaining the room temperature, and then the reaction was performed for 30 minutes. Analysis by HPLC (Conditions: Shiseido Capcell Pak C18 column 250 mm × 4.6 mm; flow rate 1 ml / min; solvent water / acetonitrile = 1/1 volume ratio; temperature 40 ° C., detector UV 254 nm; analysis time 30 minutes) The reaction was terminated after confirming the complete disappearance of 2-furoylchloride. The reaction solution was filtered to react with the produced sodium chloride and remove the remaining sodium sulfide. The filtrate was distilled to give 138.11 g (yield 92%) of the desired solid sodium thiopuroate.

Example 2

After dissolving the solid obtained in Example 1 in acetonitrile (300g) and slowly added methylene chloride (500g) crystals were precipitated. This was filtered to give 127.2 g of high purity solid sodium thiopuroate.

Example 3

Step 1: Preparation of Sodium Thiofluoroate

Sodium sulfide (Na ₂ S) pentahydrate (1.2 mol, 201.65 g) was added to acetonitrile (1 L), followed by rapid stirring. 2-furoyl chloride (1.0mol, 130.53g) was added thereto over 30 minutes while maintaining the room temperature, followed by reaction for 30 minutes. The reaction was terminated after HPLC analysis in the same manner as in Example 1 to confirm that the starting material 2-furoylchloride was completely removed. The reaction solution was filtered to remove sodium chloride and sodium sulfide remaining in the reaction.

Step 2: Preparation of 7-ACF

The acetonitrile filtrate obtained in step 1 was mixed with water (5.0 L) and the pH was adjusted to 4 with phosphoric acid. 7-ACA (7-aminocephalosporinic acid; 0.67 mol) was added to the mixed solution of water and acetonitrile, and the temperature was adjusted by using sodium hydroxide and phosphoric acid to adjust the pH to 6 to 6.5. The reaction was continued until the 7-ACA was completely exhausted while maintaining the temperature of the reaction solution at 60 ° C. At this time, the pH was maintained at 6 to 6.5. Upon completion of the reaction, phosphoric acid was added while maintaining the internal temperature to slowly drop the pH to 4 to precipitate crystals. The precipitated crystals were filtered off, washed with hot water and dried to afford 149.6 g of the desired 7-ACF [3-puroylthiomethyl-7-amino-3- cefe-4-carboxylic acid].

In the present invention, an organic solvent is used as a reaction solvent, unlike water is used as a solvent in the conventional method of preparing sodium thiopuroate. As a result, not only the odor in the reaction process, which is one of the major obstacles of the conventional method, can be removed, but also inconvenience such as the need to adjust the pH during the reaction process is eliminated. In addition, since the by-products are produced in the process of manufacturing the target material can improve the quality of the product.

When sodium thiopuroate prepared according to the present invention is further purified as in Example 2 and used for the synthesis of 7-ACF, it is possible to make a product having excellent color, thereby ultimately improving the quality of ceftiofer. In particular, thiopuronic acid, which has been used as an intermediate, is a liquid compound with a toxic odor, and is easily deteriorated at room temperature, and is difficult to store and transport as it reacts with oxygen or moisture in the air to make by-products. However, sodium thiopuroate prepared according to the present invention is a solid compound that is stable at room temperature, easy to store and transport, and the manufacturing process is also simple and can be expected to reduce the cost.

Claims (4)

A method for preparing sodium thiofuroate of the general formula (I) characterized by reacting 2-furoyl chloride of the general formula (II) with sodium sulfide in an organic solvent: [Formula 2] [Formula 1] The organic solvent of claim 1, wherein the organic solvent is selected from acetonitrile, acetone, dimethyl sulfoxide, dimethylformamide, methylene chloride, 1,2-dichloroethane, methanol, ethanol, propanol, butanol, diethyl ether and diisopropyl ether. One or more methods. The method of claim 1 wherein the sodium sulfide is in anhydride, pentahydrate or dihydrate form. 4. A process according to claim 3, wherein sodium sulfide is used in an amount of 1.0 to 1.6 equivalents based on 2-furoylchloride of formula (2).